GEP-NETPhase 3ACTION-1NCT05477576
Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy
A Phase 3 study testing RYZ101, Everolimus and Sunitinib in people with GEP-NET and Gastroenteropancreatic Neuroendocrine Tumor, run by RayzeBio, Inc. at 54 sites in 8 countries.
Trial summary
This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- GEP-NET, Gastroenteropancreatic Neuroendocrine Tumor, Gastroenteropancreatic Neuroendocrine Tumor Disease
- What is being tested?
- RYZ101, Everolimus and Sunitinib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 343 participants
- Where
- 54 sitesin 8 countries
- Study dates
- 24 Mar 2022to Dec 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 ≤20%) Eastern Cooperative Oncology Group (ECOG) status 0-2. Ki67% <20% is not required for the ad hoc subcohort of the PK/ECG substudy.
- Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 6 months following Lu-177 SSA (archival tissue is not required for the ad hoc subcohort of the PK/ECG substudy). No time limit is defined between 177Lu-SSA treatment and randomization. There must be at least 1 SSTR-PET imaging-positive measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative.
- Adequate renal function, as evidenced by estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) (Levey et al. 2009)
- Adequate hematologic function, defined by the following laboratory results:
- Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets ≥75 x 109/L (75 x 103/mm3).
- Total bilirubin ≤3 x upper limit normal (ULN)
- Serum albumin ≥3.0 g/dL unless prothrombin time is within the normal range
Who cannot join
- Prior radioembolization
- Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure, left ventricular ejection fraction (LVEF) <40% or QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 ms for males and >470 ms for females.
- Resistant hypertension, defined as uncontrolled blood pressure (BP) >140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018)
- Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
- PRRT other than Lu-177 SSA (not applicable for ad hoc subcohort of the PK/ECG substudy)
- Any condition requiring systemic treatment with high-dose glucocorticoids within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study. Inhaled or topical steroids are permitted.
- Prior history of liver cirrhosis or liver transplantation
Trial locations and contacts
54 sites in 8 countries.
54 sites in 8 countries
United States32 sites
Research Facility
Atlanta, Georgia, 30322
Research Facility
Boston, Massachusetts, 02118
Research Facility
Boston, Massachusetts, 02215
Research Facility
Cleveland, Ohio, 44106
Research Facility
Columbus, Ohio, 43221
Research Facility
Duarte, California, 91010
Research Facility
Glen Burnie, Maryland, 21061
Research Facility
Houston, Texas, 77030
Research Facility
Iowa City, Iowa, 52242
Research Facility
Irvine, California, 92663
Research Facility
Jacksonville, Florida, 32224
Research Facility
Lexington, Kentucky, 40536
Research Facility
Los Angeles, California, 90095
Research Facility
Miami, Florida, 33165
Research Facility
Nashville, Tennessee, 37232
Research Facility
New Haven, Connecticut, 06510
Research Facility
New York, New York, 10029
Research Facility
New York, New York, 10065
Research Facility
Omaha, Nebraska, 68130
Research Facility
Palo Alto, California, 94305
Research Facility
Philadelphia, Pennsylvania, 19104
Research Facility
Phoenix, Arizona, 85054
Research Facility
Pittsburgh, Pennsylvania, 15232
Research Facility
Portland, Oregon, 97239
Research Facility
Rochester, Minnesota, 55905
Research Facility
Salt Lake City, Utah, 84112
Research Facility
San Francisco, California, 94143
Research Facility
Seattle, Washington, 98109
Research Facility
St Louis, Missouri, 63110
Research Facility
Tampa, Florida, 33607
Research Facility
Troy, Michigan, 48098
Research Facility
Washington D.C., District of Columbia, 20010
France6 sites
Research Facility
Clichy
Research Facility
Lille
Research Facility
Montpellier
Research Facility
Nantes
Research Facility
Vandœuvre-lès-Nancy
Research Facility
Villejuif
Belgium3 sites
Research Facility
Brussels
Research Facility
Leuven
Research Facility
Roeselare
Brazil3 sites
Research Facility
Brasília
Research Facility
Rio de Janeiro
Research Facility
São Paulo
Canada3 sites
Research Facility
London, Ontario
Research Facility
Montreal, Quebec
Research Facility
Toronto, Ontario, M4N 3M5
Netherlands3 sites
Research Facility
Amsterdam
Research Facility
Maastricht
Research Facility
Utrecht
Spain3 sites
Research Facility
Barcelona
Research Facility
Madrid
Research Facility
Zaragoza
About this study
Official title: Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy
This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity [HA]-DOTATATE.
- Conditions
- GEP-NET, Gastroenteropancreatic Neuroendocrine Tumor, Gastroenteropancreatic Neuroendocrine Tumor Disease, Neuroendocrine Tumors, Carcinoid, Carcinoid Tumor
- Being tested
- RYZ101, Everolimus, Sunitinib, Octreotide, Lanreotide
- Keywords
- Neuroendocrine Tumors, SSTR+, GEP-NET, targeted radiotherapy, Gastroenteropancreatic Neuroendocrine Tumor, RayzeBio, Actinium, Ac 225, Dotatate, Everolimus, sunitinib, octreotide, lanreotide, PRRT, alpha emitter
- Medical subject headings
- Gastro-enteropancreatic neuroendocrine tumor, Neuroendocrine Tumors, Carcinoid Tumor, Adenoma, Islet Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RYZ101Drug
RP3D as determined in Phase 1b
EverolimusDrug
Everolimus
SunitinibDrug
Sunitinib
OctreotideDrug
High-dose octreotide
LanreotideDrug
Lanreotide
| Study group | Role | What they receive |
|---|---|---|
| Phase 1b - RYZ101 | Experimental | Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design. Receives: Drug: RYZ101 |
| Phase 3 - RYZ101 | Active comparator | Actinium 225 radiolabeled somatostatin analog (SSA) for injection Receives: Drug: RYZ101 |
| Phase 3 - Standard of Care | Active comparator | Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide. Receives: Drug: Everolimus; Drug: Sunitinib; Drug: Octreotide; Drug: Lanreotide |
| Phase 3 - RYZ101, PK/ECG Substudy adhoc subcohort | Active comparator | Actinium 225 radiolabeled somatostatin analog (SSA) for injection Receives: Drug: RYZ101 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: RP3D
Incidence of DLTs during the first 56 days of study treatment will be assessed.
Measured: 56 days of study treatment
Phase 3: PFS as determined by BICR
PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs earlier.
Measured: After the target number of 143 PFS events have occurred
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2022
- Study start24 Mar 2022
- Primary completionDec 2026 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for GEP-NETStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity \[HA\]-DOTATATE.
- Masking
- None (open label)
- Enrolment
- 343 participants (actual)
Sponsor and investigators
- Lead sponsor
- RayzeBio, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Ye Yuan, MD, Study director, RayzeBio Sr. Medical Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05477576
- Sponsor's protocol ID
- RYZ101-301
- Acronym
- ACTION-1
- Status last verified
- Oct 2026
- First submitted
- 20 Jul 2022
- Last updated
- 5 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Taunk NK, Escorcia FE, Lewis JS, Bodei L. Radiopharmaceuticals for Cancer Diagnosis and Therapy: New Targets, New Therapies-Alpha-Emitters, Novel Targets. Cancer J. 2024 May-Jun 01;30(3):218-223. doi: 10.1097/PPO.0000000000000720.
PubMed 38753757
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy
- ClinicalTrials.gov ID
- NCT05477576
- Acronym / sponsor ID
- ACTION-1 / RYZ101-301
- Conditions
- GEP-NET, Gastroenteropancreatic Neuroendocrine Tumor, Gastroenteropancreatic Neuroendocrine Tumor Disease, Neuroendocrine Tumors, Carcinoid, Carcinoid Tumor
- Keywords
- Neuroendocrine Tumors, SSTR+, GEP-NET, targeted radiotherapy, Gastroenteropancreatic Neuroendocrine Tumor, RayzeBio, Actinium, Ac 225
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 343 participants (actual)
- Lead sponsor
- RayzeBio, Inc.Industry (pharma, biotech, devices)
- Study start
- 24 Mar 2022 (actual)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 28 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity [HA]-DOTATATE.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity [HA]-DOTATATE.
| Arm | Type | Receives |
|---|---|---|
| Phase 1b - RYZ101 | Experimental | Drug: RYZ101Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design. |
| Phase 3 - RYZ101 | Active comparator | Drug: RYZ101Actinium 225 radiolabeled somatostatin analog (SSA) for injection |
| Phase 3 - Standard of Care | Active comparator | Drug: Everolimus, Drug: Sunitinib, Drug: Octreotide, Drug: LanreotideInvestigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide. |
| Phase 3 - RYZ101, PK/ECG Substudy adhoc subcohort | Active comparator | Drug: RYZ101Actinium 225 radiolabeled somatostatin analog (SSA) for injection |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 ≤20%) Eastern Cooperative Oncology Group (ECOG) status 0-2. Ki67% <20% is not required for the ad hoc subcohort of the PK/ECG substudy.
- Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 6 months following Lu-177 SSA (archival tissue is not required for the ad hoc subcohort of the PK/ECG substudy). No time limit is defined between 177Lu-SSA treatment and randomization. There must be at least 1 SSTR-PET imaging-positive measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging-negative.
- Adequate renal function, as evidenced by estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) (Levey et al. 2009)
- Adequate hematologic function, defined by the following laboratory results:
- Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets ≥75 x 109/L (75 x 103/mm3).
Key exclusion criteria (7 listed)
- Prior radioembolization
- Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure, left ventricular ejection fraction (LVEF) <40% or QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 ms for males and >470 ms for females.
- Resistant hypertension, defined as uncontrolled blood pressure (BP) >140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018)
- Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
- PRRT other than Lu-177 SSA (not applicable for ad hoc subcohort of the PK/ECG substudy)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RYZ101RP3D as determined in Phase 1b | Drug | Phase 1b - RYZ101, Phase 3 - RYZ101, Phase 3 - RYZ101, PK/ECG Substudy adhoc subcohort |
| EverolimusEverolimus | Drug | Phase 3 - Standard of Care |
| SunitinibSunitinib | Drug | Phase 3 - Standard of Care |
| OctreotideHigh-dose octreotide | Drug | Phase 3 - Standard of Care |
| LanreotideLanreotide | Drug | Phase 3 - Standard of Care |
Primary outcome
Phase 1b: RP3D
Time frame: 56 days of study treatment
Incidence of DLTs during the first 56 days of study treatment will be assessed.
Phase 3: PFS as determined by BICR
Time frame: After the target number of 143 PFS events have occurred
PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs earlier.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2026.
- Derived from this study: PubMed 38753757Taunk NK, Escorcia FE, Lewis JS, Bodei L. Radiopharmaceuticals for Cancer Diagnosis and Therapy: New Targets, New Therapies-Alpha-Emitters, Novel Targets. Cancer J. 2024 May-Jun 01;30(3):218-223. doi: 10.1097/PPO.0000000000000720.
- Individual participant dataSharing planned: Yes
Related trials for GEP-NET
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Active, not recruitingPhase 3
Efficacy and Safety of 177Lu-edotreotide PRRT in GEP-NET Patients
Neuroendocrine Tumors
RecruitingPhase 2
Comparing Retreatment of 177Lu-DOTATATE PRRT Versus the Usual Treatment in Patients With Metastatic Unresectable Gastroenteropancreatic Neuroendocrine Tumors, NET RETREAT Trial
Metastatic Digestive System Neuroendocrine Tumor G1, Metastatic Digestive System Neuroendocrine Tumor G2
RecruitingPhase 1/2
Somatostatin-Receptors (SSTR)-Agonist [212Pb]VMT-alpha-NET in Metastatic or Inoperable SSTR+ Gastrointestinal Neuroendocrine Tumor and Pheochromocytoma/Paraganglioma Previously Treated With Systemic Targeted Radioligand Therapy
Somatostatin Receptor Positive, Gastrointestinal Neuroendocrine Tumors
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Lu-177-DOTATATE (Lutathera) in Combination With Olaparib in Inoperable Gastroenteropancreatico Neuroendocrine Tumors (GEP-NET)
Gastroenteropancreatico Tumors, Neuroendocrine Tumors
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ye Yuan, MD study director
RayzeBio Sr. Medical Director
54 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing RYZ101, Everolimus and Sunitinib in people with GEP-NET and Gastroenteropancreatic Neuroendocrine Tumor, run by RayzeBio, Inc. at 54 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 5 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 54 sites in United States, France, Belgium, Brazil, Canada and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1b: RP3D (time frame: 56 days of study treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05477576, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2026.